1. Field of the Invention
The present invention relates to a separating membrane having an excellent molecular size selectivity and able to remove uremic toxins in blood, which have a molecular size smaller than that of albumin, at a high efficiency while controlling the loss of not only albumin but also valuable blood proteins, which have a molecular size larger that of albumin.
More particularly, the present invention relates to an improved regenerated cellulose hollow fiber membrane for hemopurification of blood whereby, when used for hemopurification therapy, especially hemodialysis, a variety of high-molecular-weight uremic toxins having a molecular weight of 5,000 to 66,000, represented by .beta..sub.2 -microglobulin, causing hemodialysis amyloidosis, which is a complication occurring in patients suffering from a chronic renal failure or the like, can be selectively removed without loss of valuable substances having a higher molecular weight, such as albumin, in blood.
2. Description of the Related Art
In patients suffering from chronic renal failure or the like and receiving a hemopurification therapy, complications such as anemia, hypertension, pigmentation, and bone and joint troubles, are often observed, and a clarification of the causes of and research into measures against these complications are under way.
Various causes of the above complications, for example, increasing severity of the original disease, hemeostasis-maintaining reaction premised on the presence of the original disease, reaction to pharmacotherapy and an insufficient hemopurification therapy, can be considered as an exogenous cause, in general, the substance-removing capacity of a hemopurification module used in the hemopurification therapy, especially a separating membrane, can be mentioned. Namely, it is considered that uremic toxins that cannot be removed by a conventional hemopurification membrane or can be removed only in amounts much smaller than the amounts produced in the living body, accumulate and cause complications. Nevertheless, there is no example of a complication in which the generating mechanism including the identification of a disease-causing substance is fully clarified. Accordingly, a membrane capable of removing urea having a molecular weight of 60 and uremic toxins having a molecular weight of up to about 5,000, at a high efficiency, has been widely sought.
In 1985, it was first proved that, of various complications, a main cause of hemodialysis amyloidsis represented by carpal tunnel syndrome is an accumulation of .beta..sub.2 -microglobulin having a molecular weight of 11,800 [F. Gejyo et al., Biochem. Biophys. Res. Commun., 129, 701-706 (1985)]. Because of the history of hemopurification membranes before this finding, and because of an excellent capacity for removing low-molecular-weight uremic toxins such as urea and creatinine, hemopurification modules using regenerated cellulose hollow fiber membranes were widely used. These membranes, however, have an average membrane pore radius of as small as 30 angstroms or less, and thus .beta..sub.2 -microglobulin substantially cannot be removed by these membranes. Based on the concept that the hemodialysis amyloidosis is caused by an accumulation of .beta..sub.2 -microglobulin, which is due to the above-mentioned insufficient hemopurification therapy, the development of a hemopurification membrane capable of removing .beta..sub.2 -microglobulin at a high efficiency was required. At the same time, the concept of examining the curative effect while removing all substances in blood having a molecular weight lower than the molecular weight (66,000) of albumin, having a relatively low molecular weight among valuable blood proteins, has rapidly spread. Namely the molecular size range of uremic toxins to be removed has expanded to the higher molecular weight side.
In view of the above, it is obvious that the conventional hemopurification membranes having an average pore radius not larger than 30 angstroms cannot satisfy this performance requirement: a membrane having a large membrane pore radius must be used for the removal of large substances.
As the large-pore-radius hollow fiber membrane composed of regenerated cellulose, a membrane used for the separation of a virus is known (see, for example, Japanese Unexamined Patent Publications No. 58-89626, No. 58-89628, No. 59-204911 and No. 61-254202). This membrane is used for preparing a virus-free plasma as a fractionated plasma derivative from blood pooled outside the living body, and therefore the membrane has a large membrane pore radius, a membrane structure, and a hemofiltration characteristic such that valuable substances in blood, a permeation of which is not desirable through a hemopurification membrane for the therapy of chronic renal failure, such as albumin and globulin, are allowed to permeate through the membrane. Namely, a regenerated cellulose hollow fiber membrane having a pore radius between the pore radius of the above-mentioned large-pore-radius membrane and that of the conventional hemopurification membrane, and having a membrane structure and hemodialysis and hemofiltration characteristics by which the object of the present invention can be obtained, was not known.
Among synthetic polymeric membranes, there is known a protein-leaking membrane which allows a permeation of albumin, which is a valuable blood protein, resulting in a loss of the albumin.
In contrast, mainly in the field of synthetic polymeric membrane materials, an adsorption removal-depending type hollow fiber membrane to be used exclusively for the removal of .beta..sub.2 -microglobulin (see, for example, Japanese Unexamined Patent Publication No. 63-109871), and a hollow fiber membrane in which a monomolecular adsorption layer of a protein is formed on the inner surface of the hollow fiber membrane to strictly control the molecular weight-fractionating characteristic participating in filtration [Hiroshi Ohno et al., Membrane, 13 (5), 248 (1988)], have been developed.
In the conventional hollow fiber membranes, in general, regardless of the membrane material, a water-soluble substance is contained to maintain a substance permeability, and in general, glycerol is practically used for this purpose.
As the main mechanisms of the removal of uremic toxins, there can be mentioned (1) diffusion removal, (2) filtration removal, and (3) adsorption removal. Various therapeutic methods corresponding to these mechanisms have been proposed and worked, but the hemodialysis therapy depending on diffusion is currently most widely used because there are few limitations on the equipment and maintenance thereof, the fluid therapy is unnecessary, and the treatment cost is low. Nevertheless, in the above conventional membranes for the removal of high-molecular-weight uremic toxins, the removal of substances depends mainly on the filtration or adsorption mechanism, and therefore, too much technical importance is attached to the control of the sieving coefficient indicating the filtration removal capacity, and the adsorption rate and equilibrium adsorption quantity indicating the adsorption removal capacity. Thus, in hemodialysis therapy, which is the most popular hemopurification therapy, the removal by the diffusion mechanism, which is most suitable, is very difficult for these membranes. This is due to the current technical consideration that, according to the "Stokes-Einstein equation" concerning diffusion, the diffusion coefficient is small in a high-molecular-weight substance, and therefore, it is not practical to rely on the diffusion mechanism for the removal of high-molecular-weight uremic toxins.
In general-purpose hemodialysis therapy, only about 2 to about 5 l of water is removed by one treatment, although the amount of water removed differs according to the state of a renal failure patient. Therefore, even if the sieving coefficient for high-molecular-weight uremic toxins is improved, according to "the filtration mechanism" premised on the removal of water in as large an amount as 10 to 30 l, a sufficient removal of high-molecular-weight uremic toxins cannot be obtained. Namely, the conventional technique in which control of the sieving coefficient is intended is currently as a therapeutically non-general technique premised on hemofiltration therapy or hemofiltration therapy.
Even based on this non-general hemofiltration therapy or hemodiafiltration therapy as the premise, in a conventional protein-leaking membrane formed of a synthetic polymeric material, it is considered that the average membrane pore radius is increased in the absence of a sufficient examination of the hemodialysis and filtration characteristics of the membrane. Accordingly, the sieving coefficient for albumin, which is a valuable component in blood, is large and albumin is literally lost, with the result that exhaustion occurs after the hemodialysis and hypoproteinemia is often induced. Therefore, this membrane has not been used except for special clinical cases where very much advantageous results are desired despite the known defects.
It is considered that, in practice, there is no problem if the loss of albumin is less than 10 g, preferably less than 5 g, in one treatment. Accordingly in a hemodialyser used for most popular hemopurification therapy, the loss of valuable protein components is not considered significant if the sieving coefficient of the used hollow fiber membrane to albumin is not larger than 0.15. Nevertheless, a smaller screening coefficient is preferable, and the screening coefficient should be not larger than 0.10, more preferably not larger than 0.05, which requires no special care during hemodialysis. This control of the loss of albumin in the hemodialysis, however, gives rise to another problem: namely, the removal capacity for substances which must be removed, such as .beta..sub.2 -microglobulin, is lowered.
In the membrane based on the adsorption removal mechanism, much importance is attached to the selective adsorption of .beta..sub.2 -microglobulin, and therefore, the membrane is not suitable for removing other high-molecular-weight uremic toxins, and thus can be used for hemopurification only in a very limited region. Moreover, since the adsorption is irreversible, a deterioration of the hollow fiber membrane with the lapse of time cannot be avoided during use, and a removal exceeding the saturation adsorption quantity cannot be effected. Accordingly, to remove clinically sufficient amounts of substances, a considerable amount of the hollow fiber membrane is necessary, and thus the amount of blood circulated outside the body must be increased, and thus it is difficult to use this membrane in practice. Further, this membrane is not adapted to the re-use of a hemopurification module, as practiced in some countries.
Furthermore, the conventional membrane for removing high-molecular-weight uremic toxins is inferior to the conventional hemopurification membrane in the effect of removing low-molecular-weight uremic toxins such as urea and creatinine, although this defect is associated with the therapeutic method.
In the diffusion removal of substances, the membrane surface aperture ratio indicating the area ratio of void portions in the substance-permeating surface of the membrane is an important criterion, and the larger this membrane surface aperture ratio, the larger the diffusion removal capacity, assuming that the other membrane structures are the same. For simplification, the wet porosity indicating the volume ratio of void portions in the membrane can be used instead of the membrane surface aperture ratio, and it is considered that the wet porosity should be similarly increased so as to increase the diffusion removal capacity. In Japanese Unexamined Patent Publication No. 63-109871, it is stated that, to maintain a practical strength of the hollow fiber membrane, the total volume porosity corresponding substantially to the wet porosity referred to in this specification should be not larger than 75%, although the particulars thereof are not known because data of the various materials exemplified is not give in the examples.
This value, however, is not satisfactory when designing a membrane depending on the diffusion removal mechanism. Furthermore, since the diffusion removal capacity is further increased by reducing the thickness of the hollow fiber membrane, a practical strength must be maintained at a reduced membrane thickness.